This proposal describes a multidisciplinary approach to understanding the oxidative degradation of human glutamine synthetase, an important mechanism to the aging process. Glutamine synthetase is a protein important in brain function and aging. Glutamine is believed to play an important role in the central nervous system related to the metabolism of neurotransmitters. Glutamine synthetase is a very sensitive marker of many disease and aging processes, because it is particularly vulnerable to oxidation. Free radical oxidation has been attributed to the main mechanism of damage in aging and in several diseases. A loss of activity of glutamine synthetase due to conformational change, perhaps caused by oxidation, has been attributed to the aging process. Human glutamine synthetase is less stable than the bacterial counterpart, and crystallization has been the bottleneck to determining the structure of this enzyme. The recently developed cryoelectron microscopy are particularly suitable for studying non- crystalline macromolecular assemblies, and therefore, will be used to solve the three-dimensional structure of human glutamine synthetase. The combination of cryoelectron microscopy and computer modeling will resolve the structure, sheding light on the fundamental aging mechanism of this enzyme in the molecular level.